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Proteins, Peptides and Amino Acids: Role in Infant Nutrition Sophie Nutten
Proteins are the main building blocks of the body. They are polymers composed of 30 or more amino acids. Twenty different standard amino acids combine to form the proteins. Some amino acids are essential dietary compo-nents, since they are not synthetized by human metabolic processes.
Proteins are present in and vital to every living cell. They are essential for healthy growth and development and also influence major functions of the body (fig. 1). They can influence metabolic parameters (weight gain and adi-pogenic activity), presence of beneficial bacteria in the gut, risk of developing atopic dermatitis, digestive functions and the renal system.
The infant’s first year is a critical time of rapid growth and development; this rapid growth must be supported by a high rate of protein synthesis. Infant nutrition requirements are primarily satisfied by a single and highly specific food source: breast milk. The composition of breast milk is the gold standard for estimated total protein and essential amino acid requirements during in-fancy [1]. Both total protein content and concentrations of individual proteins in human milk change throughout the first year of lactation to fulfill the needs of the infant. Milk proteins are also a source of biologically active peptides, released by gastrointestinal digestion, with a positive impact on body func-tions and ultimately health [2].
Infant formulas have been designed for infants who cannot be breastfed. These infant formulas need to be similar to breast milk in their composition but also in functional outcomes, to insure appropriate growth, optimal devel-opment, maturation of the immune system and programming of the metabolic system, for example [3]. They have been evolving throughout decades along with the scientific knowledge. Protein sources and processes have been opti-mized to provide amino acid profiles very similar to those found in breast milk. More recently, clinical data showed that a lower protein content in infant formula has long-term preventive impacts on body mass index and obesity risk [4].
In addition to guaranteeing healthy growth and development of bottle-fed infants, specific infant formulas have also been designed for specific needs, by modifying their protein component.
As an example, three different types of infant formulas have been de-signed for the management of cow’s milk allergy (affecting around 5% of infants): partially hydrolyzed, extensively hydrolyzed and amino-acid-based infant formulas (fig. 2). Allergy is triggered by protein components; one way to decrease allergenicity of proteins is to modify their conformation and/or structure responsible for the allergy, by cutting proteins into peptides which are no longer able to trigger an allergic reaction.
Some partially hydrolyzed whey-based infant formulas have been clini-cally proven to prevent atopic dermatitis in infants [5], and a first-ever FDA claim has been granted for their use in infants at risk of allergy. The specific process leading to partially hydrolyzed infant formulas leads to a reduction in allergenicity of the milk proteins and generates specific immunomodulatory peptides promoting beneficial effects.
Extensively hydrolyzed infant formulas result from a different production process leading to very short peptides, which have almost lost their allergenic properties. These infant formulas have been designed for therapeutic applica-tions, offering a solution to reduce symptoms in infants allergic to cow’s milk proteins.
Finally, in case of severe allergic reactions to cow’s milk proteins, only amino-acid-based infant formulas are able to decrease symptoms because they are totally devoid of allergens.
In conclusion, proteins provided via breast milk or infant formula are es-sential components of the infant’s diet and, therefore, the specific quality, quantity and conformation of these proteins are essential to sustain safe growth and development of infants.
References 1 Dupont C: Protein requirements during the first year of life. Am J Clin Nutr
2003;77(suppl):1544S–1549S. 2 Lönnerdal B: Infant formula and infant nutrition: bioactive proteins of human milk and
implications for composition of infant formulas. Am J Clin Nutr 2014;99:712S–717S. 3 Nagpal R, Behare P, Rana R, et al: Bioactive peptides derived from milk protein and their
health beneficial potential: an update. Food Funct 2011;2:18–27. 4 Weber M, Grote V, Closa-Monasterolo R, et al: Lower protein content in infant formula
reduces BMI and obesity risk at school age: follow-up of a randomized trial. Am J Clin Nutr 2014;99:1041–1051.
5 Szajewska H, Horvath A: Meta-analysis of the evidence for a partially hydrolyzed 100% whey formula for the prevention of allergic diseases. Curr Med Res Opin 2010;26:423–437. Fig. 1. Quantity and quality of human breast milk protein influences all as-
pects of growth as well as short- and long-term health. Fig. 2. Infant formula designed for allergy management (modification of pro-
tein conformation and structure).
Hydrolyzed Proteins in Allergy Silvia Salvatore and Yvan Vandenplas
Hydrolyzed proteins are used worldwide in the therapeutic management of infants with allergic manifestations and have long been proposed as a die-tetic measure to prevent allergy in at-risk infants.
Cow’s milk (CM) allergy (CMA) is the most frequent food allergy in early childhood and affects about 0.5–6% of infants, but the disease range varies according to patient selection, type of feeding (breast- or bottle fed) and criteria of diagnosis (symptom based or challenge proven) [1]. CM presents two different fractions of proteins: casein and whey, with both having aller-genic properties. Immunoreactive epitopes and peptide fragments of both β-lactoglobulin and casein have been well characterized [2]. Milk allergenicity is reduced by various processes but mainly by hydrolysis. Hydrolyzed formu-las (HFs) differ according to the methods of hydrolysis (such as enzymatic hydrolysis, ultraheating, ultrafiltration, pressure and glycation), the timing of hydrolysis, the degree of hydrolysis (i.e. intact protein molecules are broken down into peptides of various molecular weights), the protein source (casein, whey, rice or soy) and other nonprotein components. Based on all the above-mentioned characteristics, the in vitro results and the clinical effects of one formula cannot be transferred to another one, and commercial old and new formulas, even if from the same manufacturer, are not always compara-ble. There is no general agreement on unique standards to specifically define partially (pHFs) or extensively hydrolyzed formulas (eHFs), but the distinc-tion is generally made by the molecular weight and percentage of the peptide fragments. A pHF contains peptides with a molecular weight generally <6 kDa, ranging from 3 to 10 kDa, with some commercial pHFs containing 18% of peptides >6 kDa; an eHF usually has more than 90% of peptides <3 kDa, with 1–5% of peptides >3.5 kDa [3]. In contrast, the molecular weight of whole CM protein ranges from 14 kDa (α-lactalbumin) to 24 kDa (casein) up to 67 kDa (bovine serum albumin) [2]. The weight of peptides has immune and clinical relevance because the ‘bigger’ the peptide the ‘more allergenic’ it can be. Peptides >6 kDa, and predominantly those >10 kDa, frequently act as allergens [4], but already those in the range between 0.97 and 1.4 kDa are able to bind IgE in vitro, those >1.4 kDa can produce skin reactivity and those >3
kDa can cause a type I reaction in sensitized patients [5]. pHFs have been de-veloped with the aim of minimizing the number of sensitizing epitopes within CM proteins, while at the same time retaining peptides with sufficient size and immunogenicity to possibly stimulate the induction of oral tolerance. Two different meta-analyses [6, 7] showed that a specific whey-based pHF offers a valid option for primary allergy prevention, mainly for atopic dermatitis, in high-risk infants who are not exclusively breastfed. In one meta-analysis, it significantly halves the incidence of atopic dermatitis [11 trials; summary rel-ative risk (RR) estimate 0.56, 95% CI 0.4–0.77] up to 3 years of life compared to a standard CM formula [6]. In the other meta-analysis involving 3,284 par-ticipants (1,027 in pHF and 2,257 in control groups), a reduction in all allergic diseases of 52% [5 randomized controlled trials (RCTs); RR 0.48, 95% CI 0.23–1.00] was found at 3 and 6 months of age, 38% at 12 months (4 RCTs; RR 0.62, 95% CI 0.45–0.85; number needed to treat 12) and 58% at 30–36 months (1 RCT; RR 0.42, 95% CI 0.19–0.90) compared to a standard formula [7]. For atopic dermatitis or atopic eczema (8 RCTs), using a random-effect model, the use of pHF compared with standard formula statistically signifi-cantly reduced the incidence of eczema at 1 year (4 RCTs; RR 0.68, 95% CI 0.48–0.98; I2 ¼0%), but not at 4–6 months (5 RCTs), 2 years (3 RCTs) or 30–36 months (2 RCTs) [7].
In the (so far) largest dietary intervention study (GINI) that prospectively investigated in a randomized and double-blind design the allergy-preventive effect of three different HFs compared with a standard (CM) formula in a co-hort of 2,252 infants with at least one first-degree allergic relative, a signifi-cant reduction in eczema was noted at all study points (1, 3, 6 and 10 years) when using pHF [odds ratio (OR) 0.56; 95% CI, 0.32–0.99] or a casein-based eHF (OR 0.42, 95% CI, 0.22–0.79) but not a whey-based eHF or a standard CM formula [8]. More studies are needed to determine the nutritional effect and the real benefit of pHFs in the prevention of CMA in both high- and low-risk infants.
Because pHFs contain large CM peptides that can cause severe reactions in CMA patients, pHFs are not recommended for treatment of CMA [1, 9], and CM protein-based eHF is the preferred option in CMA infants who are not breastfed [1, 9–11]. eHFs have been extensively hydrolyzed in order to de-stroy allergenic epitopes. However, the molecular weight profile only enables to differentiate protein characteristics of formulas, but does not clearly deter-mine the allergenic formula properties and clinical response that should be tested in vivo. Although lower than in pHF, residual allergenicity is present even in eHF whilst the only anallergic formulas are the elemental ones based on free amino acids that cannot determine an immune stimulation [1, 9]. Amino-acid-based formulas (AAFs) are recommended in infants who refuse or do not tolerate eHFs or in the most severe cases of CMA [1, 9, 11]. Com-pared to eHFs, AAFs have, in most countries, higher costs, different taste and possibly different long-term nutritional effects [9, 10].
There is limited evidence that the addition of probiotics (e.g. Lactobacil-lus rhamnosus GG or Bifidobacterium breve) to an eHF offers additional ben-
efit [12, 13]. In a recent prospective trial in 38 infants with CMA (confirmed by food challenge) fed for 6 months a new rice protein-based eHF (with more than 95% rice peptides <3 kDa) without lactose but enriched with pectin, lysin and tryptophan, clinical tolerance and normal growth were noted in all pa-tients [14].
The maintenance of a decreased well-balanced diet is not easy, especially in more severe cases of CMA, but is mandatory for each child. The choice of the eHF should be based on scientific evidence of efficacy, tolerance and nu-tritional adequacy [10].
References 1 Koletzko S, Niggemann B, Arato A, et al: Diagnostic approach and management of cow’s
milk protein allergy in infants and children: ESPGHAN GI Committee practical guide-lines. J Pediatr Gastroenterol Nutr 2012;55:221–229.
2 Tsabouri S, Douros K, Priftis KN: Cow’s milk allergenicity. Endocr Metab Immune Dis-ord Drug Targets 2014;14:16–26.
3 Vandenplas Y, Bathia J, Shamir R, et al: Hydrolyzed formulas for allergy prevention. J Pediatr Gastroenterol Nutr 2014;58:549–552.
4 Aas K: What makes an allergen an allergen? Allergy 1978;33:3–14. 5 Terracciano L, Isoardi P, Arrigoni S, et al: Use of hydrolysates in the treatment of cow’s
milk allergy. Ann Allergy Asthma Immunol 2002;89(suppl 1):86–90. 6 Alexander DD, Cabana MD: Partially hydrolyzed 100% whey protein infant formula and
reduced risk of atopic dermatitis: a meta-analysis. J Pediatr Gastroenterol Nutr 2010;50:422–430.
7 Szajewska H, Horvath A: Meta-analysis of the evidence for a partially hydrolyzed 100% whey formula for the prevention of allergic diseases. Curr Med Res Opin 2010;26:423–437.
8 von Berg A, Filipiak-Pittroff B, Krämer U, et al: Allergies in high-risk schoolchildren after early intervention with cow’s milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study. J Allergy Clin Immunol 2013;131:1565–1573.
9 Muraro A, Halken S, Arshad SH, et al: EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy. Allergy 2014;69:590–601.
10 Agostoni C, Terracciano L, Varin E, Fiocchi A: The nutritional value of pro-tein-hydrolyzed formulae. Crit Rev Food Sci Nutr 2016;56:65–69.
11 Fiocchi A, Schünemann HJ, Brozek J, et al: Diagnosis and rationale for action against cow’s milk allergy (DRACMA): a summary report. J Allergy Clin Immunol 2010;126:1119–1128.
12 Berni Canani R, Nocerino R, Terrin G, et al: Formula selection for management of chil-dren with cow’s milk allergy influences the rate of acquisition of tolerance: a prospective multicenter study. J Pediatr 2013;163:771.e1–777.e1.
13 Vandenplas Y, Steenhout P, Planoudis Y, et al: Treating cow’s milk protein allergy: a double-blind randomized trial comparing two extensively hydrolysed formulas with probi-otics. Acta Paediatr 2013;102:990–998.
14 Vandenplas Y, De Greef E, Hauser B; Paradice Study Group: Safety and tolerance of a new extensively hydrolyzed rice protein-based formula in the management of infants with cow’s milk protein allergy. Eur J Pediatr 2014;173:1209–1216.
Infant Formula with Partially Hydrolyzed Proteins in Functional Gastrointestinal Disorders Yvan Vandenplas and Silvia Salvatore
Partially hydrolyzed protein formulas (pHFs) are increasingly used in the prevention of atopic disease and in the management of infants with functional gastrointestinal (GI) manifestations. Nowadays, pHFs are more likely to be used by primiparous women and those breastfeeding longer, and in infants with a family history of allergy. In a Cochrane review, no serious adverse events associated with pHF were reported. Adverse events were mentioned in three studies, but none was attributed to pHF. There may be a theoretical con-cern that both absorption and metabolism of pHF is faster than of intact pro-tein formulas. Whether this has any impact on health outcome is not known. Long-term safety data are nonexistent.
A prospective double-blind, randomized crossover trial in 115 regurgi-tating infants showed a significant decrease in the mean number and volume of regurgitations with two thickened formulas, with statistically better results for pHFs. No difference was reported in stool frequency and consistency be-tween the two groups.
Data suggest that pHFs may reduce infant colics. However, dietary changes also often include a reduction in lactose and supplementation with prebiotic oligosaccharides and structured lipids with a higher proportion of sn-2-position β-palmitate, decreasing the formation of calcium soaps. No ran-domized clinical trials have been performed demonstrating the efficacy of partially hydrolyzed protein as single change in the formula in infantile colic. Experience has shown that pHF can be a useful option when cow’s milk pro-tein allergy is not a potential cause of the colic. In fact, various randomized controlled trials demonstrating the efficacy of pHFs have been published. However, the role of (reduced) lactose can be questioned, as soy formula was not associated with a decrease in infantile colic. There are insufficient data to recommend pHF as single dietary intervention in colicky infants as most studies included other dietary changes as well.
Constipation is more frequent in casein- than in whey-predominant for-mulas. pHFs result in more frequent and softer stools in nonconstipated in-
fants. Significantly more stools were passed by breastfed infants and infants fed extensively hydrolyzed formula versus those receiving standard or soy-based formulas. Infants receiving breast milk or an extensively hydro-lyzed formula had twice as many stools as the other formula groups. GI transit time is shorter in preterm infants fed pHF than in those fed standard formula. pHFs had a markedly shorter GI transit time (9.8 h) than standard infant for-mula (19 h). pHFs, fortified with pre- and/or probiotics, with high sn-2 palmi-tate in the fat blend or without palm oil as the main source of fat in the oil blend, have been tested lately and seem to offer a good alternative for manag-ing functional constipation in infancy. There are no studies evaluating the ef-ficacy of pHF as single intervention in constipated infants.
In infants with minor GI problems such as infantile colic, regurgitation and/or constipation who were fed for 14 days with a formula containing a mixture of oligosaccharides, partially hydrolyzed whey protein and low levels of lactose and palmitic acid in the β-position, a reduction in the frequency of colics and regurgitation was reported in 79 and 70% of infants, respectively, whereas an increase in defecation was noticed. Testing the same formula in 267 infants with infantile colic, the authors demonstrated a statistically signif-icant decrease in colic episodes after 1 and 2 weeks compared to standard formula and simethicone.
In conclusion, based on the limited available literature, pHFs tend to have some beneficial effect on functional GI manifestations such as regurgitation and constipation, although the evidence is insufficient to formulate a recom-mendation.
Suggested Reading Vandenplas Y, Cruchet S, Faure C, et al: When should we use partially hydrolysed formulae for
frequent gastro-intestinal symptoms and allergy prevention? Acta Paediatr 2014;103:689–695.
Vandenplas Y, Alarcon P, Alliet P, et al: Algorithms for managing infant constipation, colic, regurgitation and cow’s milk allergy in formula-fed infants. Acta Paediatr 2015;104:449–457.
Vandenplas Y, Dupont C, Eigenmann P, et al: A workshop report on the development of the Cow’s Milk-related Symptom Score awareness tool for young children. Acta Paediatr 2015;104:334–349.
Hydrolyzed Proteins in Preterm Infants Thibault Senterre
Prematurity occurs during a critical period of development with the most rapid rate of growth in lifespan. The adequacy of nutritional support, in par-ticular protein intakes, plays an important role in many short- and long-term outcomes. Proteins are the major driving force of growth and represent the major functional and structural components of the human body. Their proper-ties and functions depend on the structure of their amino acid (AA) polypep-tide chains. Body proteins are constantly degraded and synthesized to and from AAs and protein turnover is very high in preterm infants compared to older infants, children and adults. It implies that the AA pool of the body is in constant equilibrium with potential instabilities and adverse effects of either insufficient or excessive AA concentrations.
Postnatal enteral nutrition is essential to enhance gastrointestinal matura-tion and postnatal development, but feeding problems are very frequent in preterm infants. These infants frequently suffer from postnatal feeding intol-erance and sometimes develop severe gastrointestinal diseases such as ne-crotizing enterocolitis. Human milk is considered the preferred source of nu-trients for preterm infants but is not always available. Thus, the industry has developed specially designed formulas for preterm infants (PTFs, preterm infant formulas).
Most infant formulas are developed from cow’s milk after several adapta-tions to meet the infants’ requirements. Most of them contain intact cow’s milk proteins. Extensively and partially hydrolyzed protein formulas (HPFs) have been developed to treat cow’s milk protein allergy or to prevent allergic sensitization. These formulas are also proposed and used when facing several digestive and behavioral problems in infants. Thus, for different kinds of rea-sons, term infants’ HPFs have also been used in preterm infants, and the in-dustry has also developed specific PTFs with hydrolyzed proteins (HPs).
Few studies have been published evaluating the use of HPs in preterm infants. Most studies included varying sources of protein, varying degrees of protein hydrolysis and varying nutrient contents. These studies demonstrated that the protein source plays an important role in nutritional adequacy and that adequate sources need to be used in PTFs. Protein utilization and effi-ciency is generally lower for HPs. When protein intake is similar, a lower weight gain is generally observed with PTFs and a 10% increase in protein
content is usually necessary to compensate for this reduction in protein uti-lization. Mineral absorption may also be reduced, and no data exist for trace elements and vitamins.
HPFs have also been proposed in preterm infants in order to improve their feeding tolerance. Most HPFs are associated with accelerated gastroin-testinal transit time and softer stools, but without clear benefit on feeding tol-erance. Preterm infants seem to be at similar risk of allergic diseases than term infants, but the preventive effect of HPFs has not been sufficiently explored especially in preterm infants.
In conclusion, the quantity and the quality of protein intakes play a major role in preterm infants. Most modern HPFs designed for preterm infants are well tolerated and have adapted their nutrient content to improve nutrient ab-sorption and retention. However, their benefits and safety have not been demonstrated and further high-quality studies are needed.
Hydrolyzed Formula for Every Infant? David M. Fleischer, Carina Venter and Yvan Vandenplas
Hydrolyzed formulas (HFs) are presently used primarily in infants that cannot be exclusively breastfed and those with documented cow’s milk (CM) allergy, and for primary prevention of allergic disease. HFs are increasingly being used worldwide (table 1), begging the question if HFs may be recom-mended as the optimal choice for all standard-risk, full-term infants who are not exclusively breastfed.
From the regulatory standpoint, all extensively HFs (eHFs) in the United States and Canada are approved for use only under physician supervision, thus not approved or commercialized for routine use in healthy infants. Only one of the partially HFs (pHFs) which contains 100% whey partially hydrolyzed with trypsin is approved, marketed and commercialized as a routine-use infant formula for healthy term infants. In Europe, eHFs fall under the category of food for special medical purposes, also meant for use under medical supervi-sion, but pHFs in Europe have been commercialized for routine use for a number of years. However, the most recent directive from the European Food Safety Authority states that only pHFs containing 100% whey using a specific hydrolysis process are appropriate for use as routine formulas for healthy term infants.
Data regarding the nutritional adequacy of modern-day HFs are scarce and lack long-term data suggesting that growth in infants fed HF versus intact protein formula (IPF) is different. There may be theoretical concern that par-tially hydrolyzed protein is both absorbed and metabolized faster than intact protein; whether this has any impact on the health outcomes of infants is un-known, but available data from eHFs are reassuring.
While human breast milk is the optimal source of nutrition for multiple reasons, a 2006 systematic review determined there were no comparable long-term studies regarding the prolonged use of HFs versus breastfeeding [1]. There are studies, however, that have examined the use of various formulas as a primary source or supplement to reduce the risk of atopic disease. Me-ta-analyses of formula consumption and the risk of atopic dermatitis (AD) have found that infants fed pHF compared to IPF had a lower risk of AD [2, 3], but there are significant limitations to these studies, making conclusions about the general use of HFs problematic. Some of the strongest evidence for
use of HFs for allergy prevention comes from the German Infant Nutritional Interventional (GINI) study, which followed 945 high-risk newborn infants in a randomized trial investigating the effects of breastfeeding supplemented with one of four formulas, CM, whey-based pHF (pHF-W), whey-based eHF (eHF-W) or casein-based eHF (eHF-C), in the first 4 months of life [4]. Feed-ing with either pHF-W or eHF-C had a preventive effect on the cumulative incidence of AD in high-risk children that lasted until 10 years, the current point of published data; however, it should be noted that the primary preven-tive effect on AD by using either pHF-W or eHF-C was seen within the first 2 years of life, with no significant change in effect in the remaining 8 years. Additional trials are needed in high-risk infants to confirm these findings.
Costs should be considered in decision-making regarding the choice of the formula, but global comparison of this is difficult given large cost differ-ences in different countries. Data suggest that pHF given to infants who are not exclusively breastfed is a cost-effective intervention for the prevention of atopic disorders, such as AD [5], though the question has been raised that the impact of allergy prevention in studies using HFs is limited to AD prevention, which implies that these preventive effects cannot be generalized to other al-lergic diseases in the atopic march, such as asthma and allergic rhinitis.
Despite the issues raised here (table 2), the desire to provide concrete recommendations of widespread HF use needs to be assessed carefully so as not to overstate claims of benefit. Long-term studies are needed to investigate the feasibility of HF as a routine feeding option for healthy, standard-risk in-fants. Because of the paucity of data for pHFs or eHFs, the routine use of HFs for every infant as an equivalent option to breastfeeding or IPF cannot be supported at present based on available scientific evidence.
References 1 Osborn DA, Sinn J: Formulas containing hydrolysed protein for prevention of allergy
and food intolerance in infants. Cochrane Database Syst Rev 2006;4: CD003664. 2 Alexander DD, Cabana MD: Partially hydrolyzed 100% whey protein infant formula and
reduced risk of atopic dermatitis: a meta-analysis. J Pediatr Gastroenterol Nutr 2010;50:422–430.
3 Szajewska H, Horvath A: Meta-analysis of the evidence for a partially hydrolyzed 100% whey formula for the prevention of allergic diseases. Curr Med Res Opin 2010;26:423–437.
4 von Berg A, Filipiak-Pittroff B, Kramer U, et al: Allergies in high-risk schoolchildren after early intervention with cow’s milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study. J Allergy Clin Immunol 2013;131:1565–1573.
5 Spieldenner J, Belli D, Dupont C, et al: Partially hydrolysed 100% whey-based infant formula and the prevention of atopic dermatitis: comparative pharmacoeconomic analyses. Ann Nutr Metab 2011;59(suppl 1):44–52.
Table 1. Select pHFs and eHFs available globally for infants (2015)
Country Nestlé Abbott Mead Johnson pHFs eHFs pHFs eHFs pHFs eHFs
USA pHF-W:
Gerber® Good Start® Gentle/Soothe/ Gentle for Supplementing
eHF-W: Gerber® Extensive HATM
pHF-WC:Similac® Total ComfortTM
eHF-C: Similac Expert Care® Alimentum®
pHF-WC: Enfamil® GentleaseTM/RegulineTM
eHF-C:Pregesti Nutramigen®
Canada Good Start Nutramigen China NAN HA Althéra/Alfaré Similac total
Comfort Enfamil Qingshu Nutramigen
Mexico Nan HA 1/ NAN HA 2
Althéra/Alfaré Alimentum Enfamil HA Pregestimil/ Enfamil Nutramigen
Italy NIDINA HA Althéra/Alfaré N/A N/A (discontinued)
Nutramigen/ Pregestimil
France GUIGOZ HA Althéra/Alfaré N/A N/A (discontinued) Nutramigen Germany BEBA HA Althéra/Alfaré N/A Nutramigen Nordic countries
NAN HA Althéra/Alfaré Nutramigen/ Pregestimil
Poland NAN HA Enfamil HA Digest Spain NAN HA Althéra/Alfaré Nutramigen/
Pregestimil Switzerland BEBA HA Althéra/Alfaré N/A Russia NAN HA Alfaré/‘Alfaré
Allergy’ – brand name for Althéra
Similac HA Nutramigen
Table 2. Should HFs be considered for routine use in healthy, term infants who cannot be breastfed?
Point of debate
Pro Con
Regulatory status
Per US, Canadian and European regulatory agencies, pHF-W meets requirements for routine use Other HFs do not
Data for many HFs are outdated, and hydrolyzation methods have changed, resulting in different HF compositions; therefore, data on modern-day HFs as a category are lacking
Allergeni- city
Europe: pHFs and eHFs considered ‘hypoallergenic’ North America: pHF-W may claim allergy risk reduction
Europe and North America: eHFs not for routine use even if demonstrated efficacy for allergy risk reduction or management of CM allergy Always for use under medical supervision
Metabolism The metabolic consequences of different peptide formations in HFs from industrial hydrolysis are unknown, but based on published data, there is insufficient evidence to consider HFs as potentially harmful to term infants
New peptides with unknown functions are formed during industrial hydrolysis, and peptides normally formed by digestion of milk proteins may be absent, which could result in different bioactive peptides with different effects
Absorption Adequate short-term growth has been demonstrated for all or most current HFs Select HFs have well-documented growth studies and health follow-up for up to 10 years No adverse safety issues identified by regulatory agencies
Long-term data are insufficient regarding absorption, blood metabolites and hormonal responses of various HFs vs. breastfeeding In preterm infants, weight gain rates were lower with older HFs
Gastric emptying
In term infants, some HFs induce gastric emptying closer to breast milk than IPFs In preterm infants, decreased transit time promoted feeding
Some HFs likely result in faster gastric emptying based on several small studies, which may negatively affect gastric digestion
Point of debate
Pro Con
tolerance
Gut maturation
There are insufficient data to conclude that HFs delay gut maturation compared to IPFs
There are insufficient data to conclude that HFs accelerate gut maturation compared to IPFs
Allergy prevention
If breastfeeding is insufficient or not possible for the first 4–6 months of life, the use of certain HFs has been shown to reduce the risk of developing AD in high-risk infants
While some studies have not shown a beneficial effect with the use of certain HFs for allergy prevention, systematic review and meta-analysis generally support their use
Cost- effectiveness
There are sufficient data to suggest that pHF-W given to formula-fed infants at high risk for AD is cost-effective for the prevention of AD in several countries
Studies not done for most HFs The costs of formulas vary significantly among countries, making it difficult to incorporate this into a global decision-making process
The Benefits of Breast Feeding Raanan Shamir
Human milk is considered as the gold standard for infant feeding [1, 2]. The advantages of breast feeding for infants are summarized in table 1. The multitude of studies and accumulated evidence for the benefits of breast-feeding are largely based on observational studies, and only one prospective study, PROBIT (Promotion of Breastfeeding Intervention Trial), was per-formed using a cluster randomized design comparing populations where promotion of breastfeeding was exercised. In this review, the current knowledge on some of the effects of breastfeeding on the health outcome of breastfed full-term infants will be discussed briefly.
Infections
Breastfeeding reduced the risk of gastroenteritis by 64% and of otitis me-dia by 23% [2]. In a recent Cochrane review, based on PROBIT, comparing exclusive breastfeeding for 6–7 versus 3–4 months, there was a risk ratio of 0.67 for having an episode of acute gastroenteritis at 12 months of age [3]. Also, there was a reduced risk of hospitalization due to respiratory illness (risk ratio 0.75).
Neurodevelopmental Outcome
Many publications (usually based on observational studies) demonstrate better neurodevelopment of breastfed infants compared to formula-fed infants [1, 2, 4].
In the only prospective randomized study (PROBIT) in infants at the age of 6.5 years, the intervention group had significantly higher adjusted outcomes of intelligence scores and teacher’s ratings. However, further observational studies provide contradictory results that could be explained either by con-founders or by genetic predisposition to the effects of breastfeeding.
Allergy
Observations with respect to the benefit of breastfeeding in reducing the risk of atopic diseases are available already from a study published in 1936, where a 9-month follow-up of more than 20,000 children found a 7-fold re-duction in the incidence of eczema in breastfed infants [1]. Ever since, studies have provided conflicting results, including studies demonstrating a protec-tive effect, no effect and even an increased risk of allergic disorders in breastfed infants [1, 5]. These contradictory results could be explained by confounding factors, including, among many others, the inability to control for maternal diet, partial breastfeeding, introduction of solids, inconsistent diagnostic criteria for allergic diseases as well as reverse causality (mothers to high-risk infants may tend to breastfeed) [1].
Celiac Disease as a Model for Autoimmune Disorders
Since 2012, a plethora of evidence arising from observational and inter-vention studies was published, including 2 intervention trials. Based on those data, there is no significant effect of breastfeeding, or breastfeeding at the time of gluten introduction, on the risk of developing celiac disease.
Closing Remarks
One should be cautious in interpreting the evidence that is based on ob-servational cohorts and intervention studies where breastfeeding effects were not the primary outcome. Furthermore, the only intervention study (PROBIT) with breastfeeding effects as the primary outcome measure was unable to show significant positive effects on many chronic diseases due to the lack of power to detect differences. These include the effects of breastfeeding on au-toimmune disorders as well as other diseases where observational studies demonstrated an effect, such as cancer, sudden infant death syndrome as well as other diseases (listed in table 1) not mentioned in this review.
Human milk is the preferred food and breastfeeding is the preferred feeding method for infants, with added value in premature infants. Thus, one should look at the whole spectrum of benefits, proven and unproven health outcome measures as well as other advantages (for example psychological ones), recognize the limitations of research on breastfeeding, and continue to protect, promote and support breastfeeding [1].
References 1 Agostoni C, Braegger C, Decsi T, et al: Breast-feeding: a commentary by the ESPGHAN
Committee on Nutrition. J Pediatr Gastroenterol Nutr 2009;49:112–125. 2 Breastfeeding and the use of human milk. Section on breastfeeding. Pediatrics
2012;129:e827–e841. 3 Kramer MS, Kakuma R: Optimal duration of exclusive breastfeeding. Cochrane Database
Syst Rev 2012;8:CD003517.
4 Dieterich CM, Felice JP, O’Sullivan E, Rasmussen KMl: Breastfeeding and health out-comes for the mother-infant dyad. Pediatr Clin North Am 2013;60:31–48.
5 World Health Organization, UNICEF: Protecting, Promoting and Supporting Breast-Feeding. The Special Role of Maternity Services. http://www.who.int/nutrition/publications/infantfeeding/9241561300/en/.
Table 1. Health benefits of breastfeeding to the child Infections Otitis media Respiratory infections
Lower respiratory tract Respiratory syncytial virus bronchiolitis
Upper respiratory tract Gastrointestinal tract
Neurodevelopmental outcome
Obesity
Allergy Asthma Wheezing Atopy Atopic dermatitis Eczema
Others Sudden infant death syndrome Gastrointestinal diseases
Necrotizing enterocolitis Celiac disease Inflammatory bowel disease Crohn’s disease
Chronic diseases Diabetes mellitus type 1 Diabetes mellitus type 2 Cardiovascular disease
High blood pressure Serum cholesterol
Childhood leukemia Acute lymphocytic leukemia Acute myelogenous leukemia
Protein Evolution of Human Milk Le Ye Lee, Frédéric Destaillats and Sagar K. Thakkar
Given the documented short- and long-term advantages of breastfeed-ing, human milk as a sole source of nutrition for the first few months of life is considered a normative standard. Each macroconstituent of human milk plays a crucial role in growth and development of the baby. Lipids are largely responsible for the provision of more than 50% of the energy as well as for essential fatty acids and minor lipids that are integral to all cell mem-branes. Carbohydrates can be broadly divided into lactose and oligosaccha-rides, which are readily digestible sources of glucose and indigestible nonnutritive components, respectively. Proteins in human milk provide es-sential amino acids, which are indispensable for the growth of infants. What is more interesting is that protein concentration profoundly changes from colostrum to mature milk. In this report, we share data from an observation-al, single-center, longitudinal trial assessing the constituents of human milk collected 30, 60 and 120 days postpartum from 50 mothers (singleton deliv-eries of 25 male and 25 female infants). Human breast milk is highly dy-namic [1–3] and has been shown to vary with the timing of expression, the side of the breast and the phase of the lactation cycle. These confounders were reduced in the study carried out by having early morning expression from the same side for each study subject. The breast milk was analyzed with the Miris milk analyzer for its energy, fat, carbohydrate as well as pro-tein contents, and results were also confirmed using appropriate methods. The protein content decreased with evolving stages of lactation from an av-erage of 1.45 to 1.38 g/100 ml (fig. 1). In contrast to our previous study [4] showing gender differences for lipid content 120 days postpartum, we did not reveal any gender differences in this trial. This finding was consistent with the previous literature on protein evolution of human milk during the first year of lactation. Despite the low protein content in breast milk, both groups of girls and boys managed to achieve normal growth during the study period regarding weight, height and also head circumference as per the World Health Organization Child Growth Standards [5, 6]. Further work will be performed to analyze the dietary intake of the lactating mothers and to assess the macronutrients of breast milk as well as the other breast milk components.
References 1 Lammi-Keefe CJ, Ferris AM, Jensen RG: Changes in human milk at 0600, 1000, 1400,
1800, and 2200 h. J Pediatr Gastroenterol Nutr 1990;11:83–88. 2 Lönnerdal B, Forsum E, Hambraeus L: A longitudinal study of the protein, nitrogen, and
lactose contents of human milk from Swedish well-nourished mothers. Am J Clin Nutr 1976;29:1127–1133.
3 Kent JC, Mitoulas LR, Cregan MD, et al: Volume and frequency of breastfeedings and fat content of breast milk throughout the day. Pediatrics 2006;117:e387–e395.
4 Thakkar SK, Giuffrida F, Cruz-Hernandez C, et al: Dynamics of human milk nutrient composition of women from Singapore with a special focus on lipids. Am J Hum Biol 2013;25:770–779.
5 The WHO Multicentre Growth Reference Study Group (MGRS). Geneva, WHO, 2006. 6 The WHO Child Growth Standards. Geneva, WHO, 2006.
Fig. 1. Human protein content in breast milk collected from Singaporean women over time.
Metabolic Programming: Effects of Early Nutrition on Growth, Metabolism and Body Composition Ferdinand Haschke
Effects on Growth
Accelerated weight gain during infancy and early childhood is a strong predictor of childhood and adult obesity. Meta-analyses indicate that rapid weight gain in infancy explains 20–30% of the obesity risk in the adult popu-lation [1, 2]. Breastfeeding, in particular exclusive breastfeeding during the first 4–6 months of life and continuation of breastfeeding during the second half of infancy, seems to protect from obesity in child- and adulthood [3]. The WHO has published global growth standards [4] which are based on longitu-dinal data of predominantly breastfed (>6 months) children whose mothers were not malnourished (i.e. BMI 18–25). Weight from 4 months to 2 years is lower in the WHO standards than in international growth references, which are based on data from both formula- and breastfed children. The WHO growth standards are now used in most countries of the world. Longitudinal randomized clinical trials indicate that children who are fed infant and fol-low-up formulas with protein concentrations >2.25 g/100 kcal (high protein formulas) during the first year of life grow faster than indicated by the WHO standards [5–8]. How can we slow accelerated growth in formula-fed infants? The best way is to promote breastfeeding. If breastfeeding is not possible, a meta-analysis [5] now indicates that infants fed a formula with protein of 1.8 g/100 kcal (modified whey) during the first 4 months can grow according to the WHO standards – i.e. like breastfed infants. Two longitudinal randomized trials show that infants receiving low protein formulas with modified whey protein (1.6–1.8 g/100 kcal) between 3 and 12 months have lower weight for age and slower weight gain than infants fed high protein formulas [7, 8].
Effects on Biomarkers
Biomarkers which are indicators of growth, such as IGF-1, insulin, C-peptide and branched-chained amino acids, are higher in infants receiving
high protein formulas than in breastfed infants or infants fed low protein for-mulas [7, 9]. The IGF axis regulates early growth and influences adipose tis-sue differentiation and early adipogenesis. The branched-chained amino acids leucine, isoleucine and valine are physiologic stimulators of insulin secretion. High protein intake of infants fed formula stimulates the IGF axis and insulin release, which is associated with a higher weight-for-length and BMI at the age of 2 years. Recently, it has been discussed that lower β-oxidation of fatty acids in infants who are fed high protein formulas might result in higher early weight gain and increased body fat deposition.
Effects on Body Composition
Estimation of fat mass (FM) and fat-free mass (FFM) allows more de-tailed insights into both quantitative and qualitative weight gain during or after feeding high or low protein formulas. A randomized controlled trial in infants who were fed high or low protein formulas from birth indicates that FM at 6 months (isotope dilution) correlates with BMI and weight gain velocity [10]. In infants of overweight and obese mothers who were fed high or low protein formulas, weight gain between 3 and 12 months and weight at 12 months were significantly higher in the group fed the high protein formula. Percent FM and FFM were similar at 12 months (dual energy X-ray absorptiometry) [7]. One randomized prospective study in an unselected US population has longitudinal data on infants fed high or low protein formulas. Children were followed until 60 months of age. Weight gain and composition of weight gain (FM and FFM in grams; Pea Pod) from 3 to 6 months were similar when the infants were exclusively fed the formulas. During follow-up, children who had the high protein formula gained significantly more fat from 6 to 36 months and from 6 to 60 months (dual energy X-ray absorptiometry) [8; unpubl. data].
Conclusions
Quantitative and qualitative growth indicators are among the most sensi-tive biomarkers to monitor long-term effects of early nutrition on child health. Several studies now indicate that the growth of children can be influenced by early nutrition. Breastfeeding and the use of low protein formulas in those infants who cannot be breastfed can help to prevent accelerated growth during infancy and early childhood. In addition, fat gain until 5 years is lower in children who had been breastfed or fed a low protein formula. It is most im-portant that the new low protein formulas are safe and adequate for the whole infant population. Based on new protein technologies, their essential and branched-chained amino acids are now closer to breast milk.
References 1 Nettleton JA, Jebb S, Risérus U, et al: Role of dietary fats in the prevention and treatment
of the metabolic syndrome. Ann Nutr Metab 2014;64:167–178.
2 Druet C, Stettler N, Sharp S, et al: Prediction of childhood obesity by infancy weight gain: an individual-level meta-analysis. Paediatr Perinat Epidemiol 2012;26:19–26.
3 Dewey KG, Heinig MJ, Nommsen LA, et al: Breast-fed infants are leaner than formula-fed infants at 1 y of age: the DARLING study. Am J Clin Nutr 1993;57:140–145.
4 WHO: The WHO Child Growth Standards: Length/Height-for-Age, Weight-for-Age, Weight-for-Length, Weight-for-Height and Body Mass Index-for-Age. Geneva, World Health Organization, 2006, http://www.who.int/childgrowth/standards/en/.
5 Haschke F, Grathwohl D, Detzel P, et al: Postnatal high protein intake can contribute to accelerated weight gain of infants and increased obesity risk; in Baetge EE, Dhawan A, Prentice AM (eds): Next-Generation Nutritional Biomarkers to Guide Better Health. Nestlé Nutr Workshop Ser. Basel, Karger, 2016, vol 85, pp 101–109.
6 Weber M, Grote V, Closa-Monasterolo R, et al: Lower protein content in infant formula reduces BMI and obesity risk at school age: follow-up of a randomized trial. Am J Clin Nutr 2014;99:1041–1051.
7 Inostroza J, Haschke F, Steenhout P, et al: Low-protein formula slows weight gain in in-fants of overweight mothers. J Pediatr Gastroenterol Nutr 2014;59:70–77.
8 Ziegler EE, Fields DA, Chernausek SD, et al: Adequacy of infant formula with protein content of 1.6 g/100 kcal for infants between 3 and 12 months: a randomized multicenter trial. J Pediatr Gastroenterol Nutr 2015;61:596–603.
9 Socha P, Grote V, Gruszfeld D, et al: Milk protein intake, the metabolic-endocrine re-sponse, and growth in infancy: data from a randomized clinical trial. Am J Clin Nutr 2011;94(suppl):1776S–1784S.
10 Escribano J, Luque V, Ferre N, et al: Effect of protein intake and weight gain velocity on body fat mass at 6 months of age: the EU Childhood Obesity Programme. Int J Obes (Lond) 2012;36:548–553.
Human Milk: Bioactive Proteins/Peptides and Functional Properties Bo Lönnerdal
Breastfeeding has been associated with many benefits both in the short term and in the long term. Infants being breastfed generally have less illness and have better cognitive development at 1 year of age than formula-fed in-fants. Later in life, they have a lower risk of obesity, diabetes and cardiovas-cular disease. Several components in breast milk may be responsible for these different outcomes, but bioactive proteins/peptides likely play a major role (table 1). Some proteins in breast milk are comparatively resistant towards digestion and may therefore exert their functions in the gastrointestinal tract in intact form or as larger fragments. Other milk proteins may be partially di-gested in the upper small intestine, and the resulting peptides may exert func-tions in the lower small intestine.
Lactoferrin, lysozyme and secretory IgA have been found intact in the stool of breastfed infants [1] and are therefore examples of proteins that are resistant against proteolytic degradation in the gut. Lactoferrin is the major iron-binding protein in breast milk and has been shown to bind to a specific lactoferrin receptor in the small intestine [2]. In the gut lumen, lactoferrin has bacteriostatic and bactericidal activities, and the lactoferrin receptor will facilitate the uptake of both lactoferrin and iron into the intestinal cell. In-ternalized lactoferrin can bind to the nucleus and affect the expression of genes involved in cell growth and proliferation as well as in immune func-tion. Lysozyme can kill Gram-positive bacteria but also, together with lac-toferrin in a synergistic fashion, Gram-negative bacteria [3]. Secretory IgA confers maternal immunity to her breastfed infant by providing antibodies towards bacteria and viruses she has been exposed to. Together, these pro-teins serve protective roles against infection and support immune function in the immature infant.
Bile salt-stimulated lipase is an active enzyme involved in lipid digestion in the upper alimentary tract [4]. This protein, however, is sensitive to proteo-lytic digestion and likely broken down in the mid- to lower small intestine as no peptides related to bile salt-stimulated lipase are found in the digesta. Milk fat globule membrane proteins have been shown to have antibacterial and an-tiviral activities. Little is known about the digestive fate of these proteins, but
they are likely more or less completely digested by the time they reach the lower small intestine.
α-Lactalbumin, β-casein, κ-casein and osteopontin are examples of pro-teins that are partially digested in the upper part of the small intestine, and the resulting peptides provide functions in the gut. Such functions include prebi-otic effects, stimulation of immune function, mineral and trace element ab-sorption and defense against infection. Eventually, however, these peptides will be digested and provide amino acids for the rapidly growing infant.
Cow’s milk proteins in infant formula will also be digested and some peptides formed have been shown to have bioactivities. In fact, due to similar-ities between some proteins in human and cow’s milk, several of these pep-tides are identical to or very similar to human milk bioactive peptides [5]. Other peptides, however, display different bioactivities. Hydrolysate formulas have already been industrially treated with proteolytic enzymes, resulting in a mixture of peptides which are relatively large in partially hydrolyzed infant formulas and smaller in extensively hydrolyzed formulas. When such formu-las are ingested and digested by the infant, many of the biologically active peptides will be hydrolyzed to amino acids or to novel small peptides (fig. 1). The activities and metabolic fate of such peptides are less known.
References 1 Davidson LA, Lönnerdal B: Persistence of human milk proteins in the breast-fed infant.
Acta Paediatr Scand 1987;76:733–740. 2 Suzuki YA, Lopez V, Lönnerdal B: Mammalian lactoferrin receptors: structure and func-
tion. Cell Mol Life Sci 2005;62:2560–2575. 3 Ellison RT 3rd, Giehl TJ: Killing of gram-negative bacteria by lactoferrin and lysozyme. J
Clin Invest 1991;88:1080–1091. 4 Hernell O, Bläckberg L: Digestion of human milk lipids: physiologic significance of sn-2
monoacylglycerol hydrolysis by bile salt-stimulated lipase. Pediatr Res 1982;16:882–885. 5 Wada Y, Lönnerdal B: Bioactive peptides released by in vitro digestion of standard and
hydrolyzed infant formulas. Peptides 2015;73:101–105.
Table 1. Bioactive proteins in breast milk Lactoferrin
Lysozyme Secretory IgA Bile salt-stimulated lipase Milk fat globu-le membrane proteins α-Lactalbumin β-Casein κ-Casein Osteopontin
Fig. 1. Schematic picture of the digestion of breast milk (BM) proteins and
peptides. Lf = Lactoferrin; Lyz = lysozyme; sIgA = secretory IgA.
Human Milk for Preterm Infants and Fortification Jatinder Bhatia
The World Health Organization, the American Academy of Pediatrics, European Society for Pediatric Gastroenterology, Hepatology and Nutrition and others, all support the feeding of human milk for all infants, including preterm infants. The benefits of human milk include immunologic, nutritional, developmental, psychological, social and economic advantages. In preterm infants, feeding of human milk is associated with a reduction in necrotizing enterocolitis and sepsis. In the long term, premature infants also demonstrate advantages in neurocognitive development.
However, there are several challenges in providing exclusive human milk feedings to meet the nutritional needs of infants with very low birth weight. These include inadequate milk supply, the variability n nutrient composition of human milk and the limitation of human milk itself. Human milk varies in volume with the method of milk expression, time of day, type of milk (fore- or hind milk) and stage of lactation. Reasons for low volumes include stress, lack of family or medical support, maternal illness, lack of a breast pump and dif-ficulties in storing and transporting milk.
Preterm infants have higher requirements than term infants, and after the milk transitions to mature milk in 2–3 weeks, the protein content is usually insufficient to meet the nutritional demands of a rapidly growing infant. Simi-larly, human milk does not have sufficient quantities of calcium, phosphorus and vitamin D to support bone health. Energy density of human milk also de-clines over time. When mother’s own milk is not available, it is recommended that donor milk be fed to infants. In the first place, donor milk is usually ob-tained from mothers who have been breastfeeding for several months and, therefore, protein and energy content are low. In addition, pasteurization alters the concentrations of some water-soluble vitamins as well as the activity of several bioactive components of human milk.
Poor growth is thus seen both with the use of unfortified mother’s own milk as well as donor milk, especially in infants with very low birth weight, making fortification of human milk a priority. In this discussion, macronutri-ent requirements of preterm infants and the composition of mother’s own milk and donor milk will be reviewed. Fortifiers, based on bovine and human milk,
fortification strategies and duration of fortification will also be discussed. Thus, using appropriate fortification methods will assist in meeting the nutri-ent requirements of these infants, while protecting the beneficial effects of human milk itself.
Protein Needs of Preterm Infants: Why Are They So Difficult to Meet? Ekhard E. Ziegler
Because of their exceedingly high rate of growth, premature infants have very high needs for all nutrients. But because protein is limiting for growth, requirements for protein are of particular importance. Requirements have been estimated by the factorial method based on the body composition of the fetus. In spite of using a somewhat different data and different methods of data analysis, Forbes [1] and Ziegler et al. [2] arrive at very similar estimates of protein needs for growth of the premature infant. Table 1 summarizes our es-timates.
Meeting these intakes is not particularly difficult if nutrients are provided by formulas. But human milk is the preferred feeding for premature infants because of its protective effects. When human milk is fed it must be fortified with nutrients, and then the variability in the composition of expressed milk seems to pose a problem. On the basis of studies carried out several decades ago using very high protein intakes, it is believed that high intakes of protein may be dangerous for premature babies [3]. To prevent protein intakes from being too high when the protein content of expressed milk should be high, the protein content of fortifiers has been kept low. This has had the result that protein intakes of preterm infants have been too low most of the time.
References 1 Forbes GB: Fetal growth and body composition: implications for the premature infant. J
Pediatr Gastroenterol Nutr 1983;2(suppl 1):S52–S58. 2 Ziegler EE, O’Donnell AM, Nelson SE, Fomon SJ: Body composition of the reference
fetus. Growth 1976;40:329–341. 3 Goldman HI, Goldman JS, Kaufman I, Liebman OB: Late effects of early dietary protein
intake on low-birth-weight infants. J Pediatr 1974;85:764–769.
Table 1. Requirements for protein and energy Body weight
500 to 700 g 700 to
900 g
900 to 1,200 g
1,200 to 1,500 g
1,500 to 1,800 g
1,800 to 2,200 g
Weight gain per day
g g/kg
013 016 020 024 026 029 021 020 019 018 016 014
Protein requirements, g/kg per day Parenteral 003.5 003.5 003.5 003.4 003.2 003.0 Enteral 004.0 004.0 004.0 003.9 003.6 003.4
Energy requirements, kcal/kg per day Parenteral 089 092 101 108 109 111 Enteral 105 108 119 127 128 131 Protein/energy, g/100 kcal 003.8 003.7 003.4 002.8 002.6 002.6
Optimizing Early Protein Intake for Long-Term Health of Preterm Infants Atul Singhal
The idea that protein intake in the preterm infant may influence, or pro-gram, the long-term health of the infant born preterm has been strongly sup-ported by several decades of research starting from the early 1980s. At the time, it was recognized that a high protein intake was required in preterm in-fants to achieve a postnatal growth rate closer to the intrauterine rate of growth of a normal fetus of the same postconceptional age, a goal regarded optimal for short- and long-term health. Subsequently, long-term follow-up of preterm infants randomized to a high protein formula (for an average of only 4 weeks after birth) demonstrated beneficial effects up to 16 years later on brain structure and function, including 10% greater volume of the caudate nucleus, higher IQ and practical benefits for cognitive function (e.g. mathematical rea-soning, numerical operations and reading comprehension) [1]. Since this early research, numerous observational studies have demonstrated an association between suboptimal nutrition in the early postnatal period (as measured by faltering growth, poor growth in head circumference and inadequate protein intake [2]) and impaired long-term neurocognitive development. Consequent-ly, international recommendations for protein intake in infants born prema-turely have increased progressively.
Nonetheless, despite the extensive observational evidence, the role of early protein intake in preterm infants for later neurodevelopment remains unclear. For instance, Cochrane reviews of randomized trials have not shown evidence supporting early amino acid administration [3] or higher versus low-er protein intake in formula-fed preterm infants for improving later neurode-velopment [4]. Therefore, although there are strong associations between early postnatal protein intake and neonatal growth, and between growth faltering and impaired later neurodevelopment, whether high protein supplementation can improve cognitive function in preterm infants remains controversial.
In contrast to the benefits for neurodevelopment, a longer-term follow-up of the same infants in the preterm nutritional trials mentioned above have suggested that faster postnatal weight gain increased later risk factors for car-diovascular disease. Infants randomized to a higher protein formula for the first 4 weeks were shown to have increased adiposity, insulin resistance,
dyslipidemia, levels of inflammatory markers and vascular endothelial dys-function up to 16 years later. These programming effects of early growth, termed the growth acceleration hypothesis, have now been demonstrated in randomized and observational studies in several preterm populations, as well as in infants born at term with both low and appropriate weight for gestation [5]. Therefore, as is common in biological systems, faster infant weight gain appears to have both benefits and costs on long-term health outcomes.
Current nutritional policy for preterm infants is based on the widely ac-cepted consensus that supporting optimal neurodevelopment is the neonatolo-gist’s highest priority. Therefore, on balance, this policy favors early admin-istration of a higher protein intake in order to improve later cognitive function, irrespective of any increase in cardiovascular risk. However, this consensus is largely based on research that has focused on infants <31 weeks of gestation and it is uncertain whether the risk-benefit ratio of faster weight gain differs for the larger, more mature, healthy preterm infants than those with extreme prematurity. Furthermore, the critical window for these effects is unknown and whether the same nutritional policy should apply after discharge is con-troversial. For instance, a randomized trial of formulas fed after discharge showed that a higher protein intake after hospital discharge, although increas-ing the rate of growth, did not have adverse effects on later body composition or cardiovascular risk factors.
This presentation will consider the role of protein intake on long-term health outcomes in infants born preterm, focusing on the risk-benefit ratio for accelerated growth and emphasizing the need for further research.
References 1 Isaacs EB, Morely R, Lucas A: Early diet and general cognitive outcome at adolescence in
children born at or below 30 weeks gestation. J Pediatr 2009;155:229–234. 2 Hay WW, Thureen P: Protein for preterm infants; how much is needed? How much is
enough? How much is too much? Pediatr Neonatol 2010;51:198–207. 3 Trivedi A, Sinn JKH: Early versus late administration of amino acids in preterm infants
receiving parenteral nutrition. Cochrane Database Syst Rev 2013;7:CD008771. 4 Fenton TR, Premji SS, Al-Wassia H, Sauve RS: Higher versus lower protein intake in
formula-fed low birth weight infants. Cochrane Database Syst Rev 2014;4:CD003959. 5 Wiedmeier JE, Joss-Moore LA, Lane RH et al: Early postnatal nutrition and programming
of the preterm neonate. Nutr Rev 2011;69:76–82.
Defining Protein Requirements of Preterm Infants by Using Metabolic Studies in Fetuses and Preterm Infants Chris H.P. van den Akker and Johannes B. van Goudoever
Amino acids and proteins form the main building blocks for fetal and neonatal growth. Despite improvements in neonatal care, including postnatal nutrition, growth faltering and suboptimal outcome after premature birth are still frequently encountered. Nutrition can partly be held responsible. Over the years, there has been a trend in delivering amino acids earlier from birth on-wards and in larger quantities. Studies showed positive results on efficacy, which was usually measured in terms of nitrogen balance (fig. 1) or stable isotope studies. Short-term safety has been questioned as parameters are dif-ficult to interpret, while long-term effects are not frequently assessed. Besides, it is unlikely that we have achieved the optimal therapy with regard to protein supplementation for premature neonates yet.
It is therefore also important to gain insight into how the developing fetus is able to metabolize amino acids and proteins, and to translate this to preterm infants of similar gestational age. Exploring fetal metabolism and growth could enhance our understanding of the challenges of postnatal development, even though the placenta can no longer adjust and filter metabolites postna-tally. Unfortunately, very little is known about fetal protein metabolism, which is also due to ethical and technical reasons. However, we hardly know how much nutrients the human fetus actually receives. Only a few studies have been performed using stable isotope techniques, which give us an indica-tion of the uptake and metabolism of amino acids in human fetuses. These studies show that a relatively large proportion of amino acids taken up are utilized for oxidation rather than solely being used for protein synthesis [1, 2]. Extrapolation of the individual amino acid uptakes to total amino acid intakes (that could serve as a basis to determine total amino acid requirements of pre-term infants of similar age) are hampered by the different metabolic fates of the individual amino acids. In addition, these studies do show that the fetal liver is capable of synthesizing large quantities of albumin, possibly even higher than is currently seen in premature infants fed current recommended intakes [3]. Theoretically, it would thus seem to be possible to improve certain
aspects of postnatal metabolism as well, as the metabolic apparatus of a prem-ature infant should ontogenetically be able to achieve a high hepatic rate of protein synthesis under optimal circumstances (as in utero). Nevertheless, we must acknowledge the complex interplay between the placenta and the fetus [4].
During the last decades, several studies have been performed in prema-ture neonates on amino acid metabolism, mostly comparing different nutri-tional regimens in terms of protein content. Protein metabolism is, however, influenced by many other factors. For example, the quality (individual amino acid composition) of the intravenous solution or enteral formula or concomi-tant energy intake could influence the efficacy of protein handling and, there-fore, the total requirements as well. Individual amino acid requirements during different stages of the postnatal course are, therefore, to be determined, of which only a start has been made. Besides, nonnutritional factors will influ-ence the requirements and tolerability of amino acids, although these are hardly ever studied. Efforts should be undertaken to study the effects of intra-uterine growth restriction, or needs during and following additional critical illnesses (besides prematurity itself) [5].
Thus, although we might attempt to determine amino acid requirements for the stable preterm infant based upon improved knowledge on both fetal and neonatal physiology, we are far from being able to predict the require-ments for specific subgroups, such as being small for gestational age or stressed infants with additional diseases. Unfortunately, only few of these factors have been unraveled. Only by gaining more knowledge on both fetal and neonatal physiology and disease, we should be able to optimize growth and functional outcome in premature infants.
References 1 Chien PF, Smith K, Watt PW, et al: Protein turnover in the human fetus studied at term
using stable isotope tracer amino acids. Am J Physiol 1993;265:E31–E35. 2 van den Akker CH, Schierbeek H, Minderman G, et al: Amino acid metabolism in the
human fetus at term: leucine, valine, and methionine kinetics. Pediatr Res 2011;70:566–571.
3 van den Akker CH, van Goudoever JB: Recent advances in our understanding of protein and amino acid metabolism in the human fetus. Curr Opin Clin Nutr Metab Care 2010;13:75–80.
4 Avagliano L, Garo C, Marconi AM: Placental amino acids transport in intrauterine growth restriction. J Pregnancy 2012;2012:972562.
5 Ramel SE, Brown LD, Georgieff MK: The impact of neonatal illness on nutritional re-quirements – one size does not fit all. Curr Pediatr Rep 2014;2:248–254.
6 Forsyth JS, Murdock N, Crighton A: Low birthweight infants and total parenteral nutrition immediately after birth. III. Randomised study of energy substrate utilisation, nitrogen balance, and carbon dioxide production. Arch Dis Child Fetal Neonatal Ed 1995;73:F13–F16.
7 Ibrahim HM, Jeroudi MA, Baier RJ, et al: Aggressive early total parental nutrition in low-birth-weight infants. J Perinatol 2004;24:482–486.
8 Rivera A Jr, Bell EF, Bier DM: Effect of intravenous amino acids on protein metabolism of preterm infants during the first three days of life. Pediatr Res 1993;33:106–111.
9 Saini J, MacMahon P, Morgan JB, Kovar IZ: Early parenteral feeding of amino acids.
Arch Dis Child 1989;64:1362–1366. 10 te Braake FW, van den Akker CH, Wattimena DJ, et al: Amino acid administration to
premature infants directly after birth. J Pediatr 2005;147:457–461. 11 Thureen PJ, Melara D, Fennessey PV, Hay WW Jr: Effect of low versus high intravenous
amino acid intake on very low birth weight infants in the early neonatal period. Pediatr Res 2003;53:24–32.
12 van Goudoever JB, Colen T, Wattimena JL, et al: Immediate commencement of amino acid supplementation in preterm infants: effect on serum amino acid concentrations and protein kinetics on the first day of life. J Pediatr 1995;127:458–465.
13 van Lingen RA, van Goudoever JB, Luijendijk IH, et al: Effects of early amino acid ad-ministration during total parenteral nutrition on protein metabolism in pre-term infants. Clin Sci (Lond) 1992;82:199–203.
14 Vlaardingerbroek H, Vermeulen MJ, Rook D, et al: Safety and efficacy of early parenteral lipid and high-dose amino acid administration to very low birth weight infants. J Pediatr 2013;163:638.e5–644.e5. Fig. 1. Correlation plot of results in different trials investigating different amino
acid intakes and nitrogen balances during the first few days of life of preterm in-fants. The size of the symbols resembles the number of infants included in the clinical trial.
Amino Acid Intake in Preterm Infants Ilaria Burattini, Maria Paola Bellagamba, Rita D’Ascenzo, Chiara Biagetti and Virgilio Paolo Carnielli
A large proportion of extremely low-birth-weight infants require paren-teral nutrition for variable lengths of time. Amino acids are the key ingredient of parenteral nutrition. The aim of appropriate amino acid administration is to promote anabolism and optimal cellular development with the final goal of reducing postnatal growth restriction, which is associated with neurodevelop-mental delays. The benefits of early amino acid commencement is compelling, especially on nitrogen balance, while long-term outcome studies are lacking. An intake of 2.5 g/kg per day of amino acids is to be preferred to lower amounts. Benefits of amino acid intakes >2.5 g/kg per day without extra en-ergy remain controversial. Two randomized controlled trials do not show ben-efits on short-term growth and neurodevelopment at the 2-year follow-up. Studies with amino acid intake >2.5 g/kg per day with extra energy are war-ranted.
List of Speakers
Prof. Jatinder Bhatia Division of Neonatology Department of Pediatrics Medical College of Georgia Georgia Regents University 1120 15th Street, BIW 6033 Augusta, GA 30912-3740 United States E-Mail [email protected] Prof. Virgilio P. Carnielli Department of Medical Sciences Polytechnic University of Marche Piazza Roma 22, 60121 Ancona Italy E-Mail [email protected] Assoc. Prof. Dr. David M. Fleischer Section of Allergy Department of Pediatrics Children's Hospital Colorado 13123 East 16th Avenue, B518 Aurora, CO 80045 USA E-Mail [email protected] Prof. Ferdinand Haschke Department of Pediatrics Landeskrankenhaus Salzburg/ Universitätsklinikum der PMU Müllner Hauptstrasse 48 5020 Salzburg Austria E-Mail [email protected] Dr. Le Ye Lee
Department of Neonatology Yong Loo Lin School of Medicine National University of Singapore NUHS Tower Block Level 12 1E Kent Ridge Road Singapore 119228 Singapore E-Mail [email protected] Dr. Bo Lönnerdal Department of Nutrition University of California 3109 Meyer Hall 1 Shields Avenue Davis, CA 95616 USA E-Mail [email protected] Dr. Sophie Nutten Nutrition and Health Research Department Nestlé Research Centre Route du Jorat 57, 1000 Lausanne 26 Switzerland E-Mail [email protected] Dr. Silvia Salvatore Pediatric Department, Ospedale F. del Ponte Via F. Del Ponte 19 21100 Varese Italy E-Mail [email protected] Dr. Thibault Senterre Department of Neonatology Centre Hospitalier Régional de la Citadelle CHU de Liège, University of Liège Boulevard du 12ème de Ligne 1 4000 Liège Belgium E-Mail [email protected] Prof. Raanan Shamir Institute for Gastroenterology Nutrition and Liver Diseases Schneider Children’s Medical Center 14 Kaplan Street Petach-Tikva 49202
Israel E-Mail [email protected] Prof. Atul Singhal The Childhood Nutrition Research Centre Institute of Child Health University College of London 30 Guilford Street London WC1N 1EH UK E-Mail [email protected] Dr. Sagar K. Thakkar Nestlé Research Centre, Nestec Ltd. Route du Jorat 57 1000 Lausanne 26 Switzerland E-Mail [email protected] Dr. Chris van den Akker Erasmus MC-Sophia Room SH-2015 Wytemaweg 80 3015 CN Rotterdam The Netherlands E-Mail [email protected] Prof. Dr. Yvan Vandenplas Department Gastroenterology KZ Universitair Ziekenhuis Brussel Campus Jette Laarbeeklaan 101 1090 Brussels Belgium E-Mail [email protected] Prof. Ekhard E. Ziegler Department of Pediatrics University of Iowa MTF 2501 Crosspark Road Coralville, IA 52241 United States E-Mail [email protected]
